3 research outputs found
A Computational Model for Overcoming Drug Resistance Using Selective Dual-Inhibitors for Aurora Kinase A and Its T217D Variant
The human Aurora kinase-A (AK-A)
is an essential mitotic regulator
that is frequently overexpressed in several cancers. The recent development
of several novel AK-A inhibitors has been driven by the well-established
association of this target with cancer development and progression.
However, resistance and cross-reactivity with similar kinases demands
an improvement in our understanding of key molecular interactions
between the Aurora kinase-A substrate binding pocket and potential
inhibitors. Here, we describe the implementation of state-of-the-art
virtual screening techniques to discover a novel set of Aurora kinase-A
ligands that are predicted to strongly bind not only to the wild type
protein, but also to the T217D mutation that exhibits resistance to
existing inhibitors. Furthermore, a subset of these computationally
screened ligands was shown to be more selective toward the mutant
variant over the wild type protein. The description of these selective
subsets of ligands provides a unique pharmacological tool for the
design of new drug regimens aimed at overcoming both kinase cross-reactivity
and drug resistance associated with the Aurora kinase-A T217D mutation
Roughness of Molecular Property Landscapes and Its Impact on Modellability
In molecular discovery and drug design, structure–property
relationships and activity landscapes are often qualitatively or quantitatively
analyzed to guide the navigation of chemical space. The roughness
(or smoothness) of these molecular property landscapes is one of their
most studied geometric attributes, as it can characterize the presence
of activity cliffs, with rougher landscapes generally expected to
pose tougher optimization challenges. Here, we introduce a general,
quantitative measure for describing the roughness of molecular property
landscapes. The proposed roughness index (ROGI) is loosely inspired
by the concept of fractal dimension and strongly correlates with the
out-of-sample error achieved by machine learning models on numerous
regression tasks
Toward a Standard Protocol for Micelle Simulation
In
this paper, we present protocols for simulating micelles using
dissipative particle dynamics (and in principle molecular dynamics)
that we expect to be appropriate for computing micelle properties
for a wide range of surfactant molecules. The protocols address challenges
in equilibrating and sampling, specifically when kinetics can be very
different with changes in surfactant concentration, and with minor
changes in molecular size and structure, even using the same force
field parameters. We demonstrate that detection of equilibrium can
be automated and is robust, for the molecules in this study and others
we have considered. In order to quantify the degree of sampling obtained
during simulations, metrics to assess the degree of molecular exchange
among micellar material are presented, and the use of correlation
times are prescribed to assess sampling and for statistical uncertainty
estimates on the relevant simulation observables. We show that the
computational challenges facing the measurement of the critical micelle
concentration (CMC) are somewhat different for high and low CMC materials.
While a specific choice is not recommended here, we demonstrate that
various methods give values that are consistent in terms of trends,
even if not numerically equivalent